How to Design a Good Case Series

Transcription

1 21 COPYRIGHT Ó 2009 BY THE JOURNAL OF BONE AND JOINT SURGERY, INCORPORATED How to Design a Goo Case Series By Bauke Kooistra, BSc, Bernaette Dijkman, BSc, Thomas A. Einhorn, MD, an Mohit Bhanari, MD, MSc, FRCSC A case series is a escriptive stuy that follows a group of patients who have a similar iagnosis or who are unergoing the same proceure over a certain perio of time. As there is no experimental protocol or control for allocation of patients to treatment, surgeons an patients ecie on whether or not treatment is given, making the clinical sample representative of a common clinical population. Results of case series can generate hypotheses that are useful in esigning further stuies, incluing ranomize controlle trials. However, no causal inferences shoul be mae from case series regaring the efficacy of the investigate treatment. This article will provie principles for the esign, analysis, an reporting of case series, illustrate by examples from the orthopaeic surgical literature. Introuction In clinical research, stuies can be classifie into escriptive an analytic stuies. Descriptive stuies are always observational stuies an escribe general isease characteristics relate to person, place, an time. They inclue cross-sectional stuies, surveillance stuies, ecological correlational stuies, case reports, an case series 1. Analytic stuies test a hypothesis about a causal relation between exposure an outcome 2. They can be observational, such as case-control an cohort stuies, or controlle, such as the ranomize controlle trial. In the ranomize controlle trial, the intervention or treatment is ranomly assigne by the researcher, while in observational stuies, the surgeon an/or the patient ecie on which treatment is given, as happens in routine care. The results of ranomize controlle trials are consiere the highest level of evience because ranomization controls for prognostic factors between two comparison groups, thereby minimizing the role of confouning bias an optimizing the internal valiity. In the hierarchy of evience, ranomize controlle trials (Level I) are followe by cohort stuies (Level II), case-control stuies (Level III), case series (Level IV), an expert opinion (Level V) 2. Even though a ranomize controlle trial carries the highest level of evience (Level I), for technical or ethical reasons, it is not an appropriate esign for all clinical questions 2-4. For example, in fracture-healing research, it woul be unethical to ranomize patients with grossly contaminate open tibial shaft fractures to either early or elaye treatment. In these situations, observational stuies are the best alternative to stuy the efficacy an safety of a certain intervention. Cohort stuies, case-control stuies, an case series are all types of observational stuies. Cohort an case-control stuies iffer from case series in that they make use of a comparison group in the analysis of the treatment effect on the outcomes. Case series belong to a group of escriptive stuies that o not test the hypothesis of treatment efficacy 4. A case series follows a group of patients who have a similar iagnosis or who are unergoing the same proceure over a certain perio of time. Although case series have methoological limitations with regar to making causal inferences about the relation between treatment an outcome, they can be helpful in generating a hypothesis that can be teste in further analytic stuies 2. This article will iscuss the main purposes an the major strengths an limitations of a case series. Principles are provie for its esign, analysis, an report. When to Consier a Case Series? Despite its negligible role in assessing treatment efficacy, a case series is suitable for a more cautious escription of interventions in several settings. First, case series serve as a means of initially reporting on novel iagnostic or therapeutic strategies, particularly when the option of waiting for comparative evience is consiere unacceptable. Secon, patient registries can be a tool for summarizing the outcomes in a certain patient category (for example, all patients with tibial fractures) 4. The primary purpose of a case series shoul be the generation of hypotheses that subsequently can be teste in stuies of greater methoological rigor. Put simply, a case series can be seen as a screening tool for sensible hypotheses that are worthy of further examination. Treatment safety an iagnostic accuracy are the principal outcomes that can be assesse fairly an reliably in a case series. In the assessment of either outcome, no control group is necessary an long-term follow-up can be obtaine reaily, especially in a retrospective esign. Information regaring the characterization of isease Disclosure: The authors i not receive any outsie funing or grants in support of their research for or preparation of this work. Neither they nor a member of their immeiate families receive payments or other benefits or a commitment or agreement to provie such benefits from a commercial entity. J Bone Joint Surg Am. 2009;91 Suppl 3:21-6 oi: /jbjs.h.01573

2 22 patterns in terms of natural history, recovery, an prognostic factors may help a researcher etermine the sample size, relevant covariates, an length of follow-up that shoul be use in a subsequent ranomize controlle trial 5. Rather than being an anteceent of more vali research, case series may also be an alternative or a valuable ajunct 4,6. Strengths an Limitations of a Case Series As with all stuy esigns, case series have strengths an limitations (Table I). Strengths In all observational stuies, incluing case series, the stuy investigators o not control which intervention(s) the research participant receives. The avantage of this approach over a ranomize controlle trial is that the stuy results are closer to those obtaine in routine clinical practice an may therefore be consiere more relevant 5,7. A higher relevance (or external valiity) means that the results can be better applie to clinical practice in other centers. Another avantage of not interfering in the treatment ecision is that the surgeons are not force to perform an operation with which they are less experience. The external valiity is also high in a case series that inclues a iverse range of patients. By incluing patients with ifferent characteristics an co-interventions, the stuy sample is more likely to be representative of the population of interest. In a ranomize controlle trial, however, relatively stringent inclusion criteria an selection of only those patients who wish to participate ecrease the extent to which the results can be applie to common clinical practice 8,9. In contrast with ranomize controlle trials, case series o not inclue a comparison group, nor is any form of ranomization employe. The case series is therefore a relatively efficient an cost-saving esign. In a case series, the ecision about the treatment regimen remains with the surgeon an the patient. This is an obvious avantage when ethical consierations prohibit the ranomization of a patient to a nontreatment group or to a treatment that woul be inconsistent with common stanars of orthopaeic practice (e.g., a placebotreatment group). TABLE I Strengths an Limitations of a Case-Series Design Strengths Limitations High external valiity No interference in treatment ecision process Wie range of patients Inexpensive Stuy conuct takes little time Lack of comparison group Data collection often incomplete Susceptible to bias Selection bias Measurement bias Limitations The primary limitation of a case series is its lack of a comparison (control) group. A control group is a group of patients who share all of the characteristics of the patients of the treatment group except that they o not receive the treatment. When a stuy lacks a control group, no causal inferences shoul be mae about the relationship between the treatment an the outcomes, since it is impossible to etermine whether the outcomes are attributable to the treatment effect or to other patient characteristics. As a result, hypotheses can only be mae about apparent relationships. A case series is often base on retrospective observation of patient ata. Conucting a case series prospectively (i.e., thehypothesispreceesatacollection) or retrospectively (vice versa) makes a ifference as to the extent of selection an measurement bias encapsulate in the observations. In contrast to the metho of operation of a ranomize controlle trial, rigorously evelope protocols an a eicate single investigator (for example, a research nurse) are absent in a retrospective esign, which may ecrease the completeness of inclusion, ata collection, an patient follow-up. Aitionally, ata are not measure in a stanarize way, thereby increasing the measurement bias. Further, the researcher is epenent on whatever outcomes have been measure in the course of routine care an cannot select a suitable an vali outcome measure as is possible in a prospective esign 7. Similar to other observational stuy esigns, case series are prone to bias. Selection bias occurs when follow-up ata are less likely to be collecte from patients with a better or worse outcome. For example, when the only subjects inclue in a stuy are those who are available for a follow-up of at least six months, patients who ie or change hospitals before six months are not inclue. These patients are likely to have ha worse outcomes than the ones who survive, so the selection of patients is therefore biase. Measurement bias can arise when ifferent methos of outcome measurement are use in a stuy. Compare with case series, measurement bias might be more likely to occur in case-control an cohort stuies, because the ifference between the treatment an control groups makes it more likely for investigators to gather information in ifferent ways. Selection an measurement bias shoul theoretically occurasmuchincaseseriesasinranomizecontrolle trials, because ranomize controlle trials only control for confouning bias 7. Confouning bias occurs in the presence of confouners, that is, factors that istort the true relationship of the stuy variable of interest by virtue of also being relate to the outcome of interest 10.Confouningbiasisnot present in case series for the simple reason that there is no control group. However, because the protocols associate with ranomize controlle trials are typically better evelope an of higher quality than those of case series with regar to methos to control for bias, selection an measurement bias may be less common in ranomize controlle trials.

3 23 Criteria for a Goo Case Series Specific guielines for planning, conucting, an reporting a case series are presente below 1,4,5,7. We recommen reporting on how each of these guielines was implemente when writing a paper on a case series 11. Design As with other stuy esigns, the stuy question shoul be focuse an appropriate for a case series. Specifically, the question shoul not be whether the investigate treatment is more effective or safer than another treatment. The stuy question shoul list (1) its stuy population, (2) the intervention, an (3) the primary outcome. The case efinition shoul mention inclusion an exclusion criteria, which shoul be base on wiely use, preferably valiate, efinitions. If authors use their own criteria, efinition an justification are necessary to enable the reaer to compare the stuie population with his or her own patients. A consecutive inclusion of patients optimizes external valiity. It may be tempting to inclue patients seen over a large perio of time to increase sample size. However, the use of a short inclusion perio minimizes known an unknown changes over time in co-interventions, prognosis, an even in the intervention uner stuy. A etaile escription of the intervention an the cointervention shoul be state. This will ensure repeatability of the stuy by other investigators. It is very important to thoroughly escribe co-interventions (for example, postoperative mobilization an physical therapy), as these are not always stanarize among stuy centers as is frequently implie by vague statements that patients receive stanarize operative or postoperative care. Aitionally, inications for the stuie treatment shoul be explaine. This will primarily etermine the consistency of the patient group. The most important outcomes in care are those that measure patient satisfaction, relief of symptoms, an a feeling of well-being. An example is the Short Form-36 questionnaire, which not only measures physical function but also mental well-being 12. Incluing only clinical measurements woul not represent the subjective nature of patient care. Further, outcomes measurements shoul be vali an reliable. Valiity refers to the egree to which the ata measure what they were intene to measure. An example of a vali measure is the Western Ontario an McMaster Universities (WOMAC) Osteoarthritis Inex, which correlates well with earlier establishe instruments of pain, stiffness, an physical function 13. Reliability refers to the extent to which repeate measurements of a stable phenomenon get similar results. The general impression of raiographic healing of tibial fractures is an example of a measurement with a high interobserver agreement 14. The blining of outcome assessors is ieal in every kin of research esign an can be implemente quite usefully in case-series stuies (e.g., by having some investigators collect ata only on outcome an others collect ata only on patient characteristics). This prevents the investigators measurements from being influence (intentionally or unintentionally) by their personal treatment preference. The metho of ata acquisition (telephone interview, clinical measurement, or chart review) shoul be aresse in the stuy report for the sake of repeatability an the appraisal of measurement bias. A further criterion of a well-measure outcome is the minimal length of follow-up. Sufficient time shoul be given for complications to evelop an be recore. For example, a maximal follow-up time of six months in a stuy of health-relate quality of life after a tibial fracture woul unerestimate the patients eventual health status, since patients continue to improve for up to a year, an sometimes longer, after the occurrence of a fracture. Analysis As the esign of a case series is escriptive, only escriptive statistics shoul be use 15. That is, no comparative tests yieling p values shoul be one. By escribing summary statistics, the author errs on the conservative sie of speculation an avois misleaing his or her colleagues with fancy probability statistics. Reporting As case series have many methoological limitations, their finings shoul be escribe. First, a statement of the external valiity of the obtaine ata shoul be given. This inclues (1) patient characteristics an (2) completeness of follow-up. Aitionally, the presence of chance an the presence, irection, an magnitue of bias shoul be acknowlege. Authors who only emphasize the resemblance to routine clinical practice greatly mislea their auience by withholing from them information on internal valiity. Patients may iffer accoring to prognostic variables, such as age, etiology, an isease severity among geographical regions. This may complicate comparisons with other reports or explain iscrepancies. For example, a relatively greater contribution of blunt trauma to all observe severe injuries in Europe may explain why the most preictive trauma score iffers from that which can be foun in North American stuies 16. The follow-up rates an reasons for loss to follow-up shoul be state. Completeness of follow-up varies consierably among similar case series 9, making it ifficult for reaers to compare them. Therefore, authors shoul be cautious when interpreting their own results in relation to results of apparently similar case series. Most importantly, no absolute conclusions on the stuie treatment shoul be state. As mentione before, the lack of a comparison group prohibits any hypothesis from being teste. Vali conclusions basically repeat the escriptive stuy finings, for example, our patients treate by treatment X showe goo outcome Y after Z months of follow-up. Stating that treatment X is better than treatment Y or even that treatment X is effective woul be invali. Inferring such a fining coul lea a reaer to use treatment X in the care of a patient, a ecision that woul seem to be evience-base but that in reality is not an coul lea to an unfavorable outcome.

4 24 Example 1: A Case Series Followe by Research with Higher Level of Evience Extrameullary fixation with a sliing hip screw has shown goo clinical results in the treatment of pertrochanteric fractures. However, because of some reporte complications, the intrameullary gamma nail, which theoretically has biomechanical avantages over a sliing hip screw, was evelope Chevalley an Gamba presente a case series of sixty-three patients who were treate for a pertrochanteric hip fracture with agammanail 20. Data for this stuy were collecte prospectively, an patients were followe until the en of treatment for an average of 7.2 months. The quality of reuction was classifie, on the basis of the raiographic fracture gap, as goo in thirtyeight patients, acceptable in nineteen patients, an unsatisfactory in six patients. On the average, full weight-bearing was allowe by the twenty-fourth ay after the proceure, an fracture consoliation was seen raiographically at an average of 3.8 months. In their iscussion, the authors state their belief that use of the gamma nail avois elays in full weight-bearing, shortens the proceure to treat unstable intertrochanteric fractures, an iminishes the risk of nonunion. Several strengths are recognize in the esign of this case series. First, the prospective nature of the stuy mae it more likely that the ata that were collecte woul be complete. Also, consecutive patients were inclue in this series. Selection bias was limite because all patients who receive treatment with gamma nails in the observe perio were inclue in the stuy. The authors justly i not overstep the goal of a case series, as their goal was to present their results with gamma nailing. However, they i not escribe their main outcomes of interest in their methos section an i not escribe the criteria that were use to assess the outcomes. Because patients were followe until the en of treatment, this stuy is complete with regar to the report for potential complications associate with the treatment. However, no efinition of the en of treatment was given by the investigators. The quality of reuction was assesse on the basis of classification of fracture-gap size as etermine by the investigators. The authors i not justify this ecision; however, they i efine the categories. The postoperative results are therefore easily interprete by reaers who may not be familiar with this type of classification. No causal inferences are mae, as the authors o not claim that gamma nails are superior to sliing hip-screw systems in general an inclue the wors in our experience in their conclusion. Also, results from other series are mentione in the conclusion, but the authors acknowlege that comparison with these series woul not be appropriate. Because a lack of consensus exists among observational stuies regaring the optimal operative treatment of pertrochanteric fractures, further stuies with a higher level of evience were neee. Several ranomize controlle trials were performe, comparing gamma-nail fixation with sliing hipscrew fixation, an a recent meta-analysis summarize the evience from these trials 21. The primary conclusion from this meta-analysis was that there was no avantage of gamma nail fixation over sliing hip-screw fixation with regar to mortality, nonunion, an complications. As a result, surgeons are now better prepare to make an evience-base ecision on the treatment of pertrochanteric fractures. Example 2: Treatment Evaluation by Functional Outcome Agreement exists on the nee for operative treatment of tibial avulsion fractures of the posterior cruciate ligament, but not on the optimal surgical approach 22,23. Nicanri et al. recently presente a retrospective case series on patients who unerwent a moifie open posterior approach 24. Their purpose was to explore long-term functional status following this new proceure, incluing clinical (Musculoskeletal Function Assessment questionnaire, posterior rawer test, an knee range of motion) an raiographic (fracture-healing) outcomes. In their introuction, the authors state that an open proceure was inicate for some patients with posterior cruciate ligament avulsion, but they i not specify their inclusion criteria. As a result, trauma surgeons are unable to appreciate the clinical relevance. The operative proceure an the postoperative treatment were very extensively escribe, an the clinical outcomes were all valiate (except for the knee range of motion, which was measure with use of the commonly use goniometer). In contrast, no efinition of raiographic healing was given. While there is controversy regaring the best metho of monitoring raiographic healing 25, at least one accepte metho shoul have been use. In this case series, the external valiity is compromise because of the retrospective stuy esign. From an alreay small sample, eight of eighteen patients were eliminate because of missing ata. The average musculoskeletal functional assessment score was 14, which is favorable. Two patients ha grae-ii laxity, an eight patients ha grae-i laxity, which is favorable as well. Only the p values of tests comparing the range of motion of the affecte an the contralateral knees were presente, rather than raw ata on affecte knee range of motion. Since the sample size is very small, no significant ifferences coul be etecte, falsely suggesting that knee functions were intact. In their iscussion, the authors use their ata to recommen the use of early postoperative mobilization. Although the authors mentione the limitations of their case series, they conclue that their operative technique results in goo clinical, raiographic an functional outcomes. Although the clinical results are believable, it is not clear to which type of patients they apply. In aition, a substantial number of patients who unerwent the proceure were exclue. Therefore, an because no control group was use, the authors conclusion that the outcomes were the result of their surgical approach is invali. Example 3: A Case Series Designe to Assess the Safety of an Intervention Operative fixation of isplace supraconylar humeral fractures in chilren is performe to maintain anatomical reuction an to minimize the complication rate associate with nonoperative management. The best approach to Gartlan 26 type- II fractures remains controversial.

5 25 Skaggs et al. conucte a case series in which the purpose was to etermine the complication rate, both surgical an anesthetic, of the operative treatment (close reuction an percutaneous pinning) of type-ii supraconylar fractures in chilren 27. Only patients with complete meical recors an a minimum follow-up of six weeks were inclue. Data were acquire from a review of raiographs an clinical notes, an patients were classifie as excellent, goo, fair, or poor on the basis of the criteria escribe by Flynn et al. 28. Accoring to these criteria, 181 patients ha excellent results, six ha goo results, an two ha fair results. There were no surgical or anesthetic complications note in this series. The primary limitation of this case series was the short follow-up perio. This case series only use a minimum of six weeks of follow-up, which woul be far too short a time for the occurrence of some surgical complications (such as nonunion) that were assigne as outcomes in this series. Furthermore, the authors were not consistent in stating the purpose of their stuy. While they emphasize etermination of the complication rate in their introuction an iscussion, their overall recommenations also containe suggestions about the efficacy of the treatment ( satisfactory outcome ). Also, selection bias might be present, since only patients with complete meical recors an a minimum of six weeks of follow-up were inclue. In the methos section, the authors provie a etaile escription of the ata that were collecte an they provie a reference for the Flynn classification system. As in all case series, the type of treatment was chosen by the surgeon, an, as a result, ifferent pin configurations were use for fixation. These ifferent configurations were properly presente in a table, which makes it easy for the reaers to juge if this series is applicable to their own practice. The authors reporte on the results of another series of similar fractures in chilren who were treate without pinning, an they use this group as a control group to conclue that initial operative treatment in their series le to a higher chance of satisfactory outcome without an increase risk of complications. However, results from ifferent case series cannot be compare, an such conclusions, as in this example, cannot be properly rawn. Summary Although a case series is lower than a ranomize controlle trial in the hierarchy of evience, it coul be useful when use of a ranomize controlle trial is not appropriate or possible. Even though no causal inferences can be mae, a case series is a goo way to generate new hypotheses about treatment efficacy an to assess information about the safety an iagnostic accuracy of a treatment. Also, the external valiity of a case series often excees that of a ranomize controlle trial. However, keeping the methoological limitations of a case series in min, one shoul be careful in applying its conclusions to clinical practice before more evience is obtaine from ranomize trials. The ieal case series woul have a prospective esign, woul contain a clear efinition of its population, the intervention, the outcomes, an the amount of follow-up, an woul not make any causal inferences about the treatment effect. When esigne an conucte in the right way, a case series can be a sensible alternative to stuies with higher levels of evience, with the aitional avantage of saving a lot of time an money. n Bauke Kooistra, BSc Bernaette Dijkman, BSc Mohit Bhanari, MD, MSc, FRCSC Division of Orthopaeic Surgery, Department of Surgery, McMaster University, 293 Wellington Street North, Suite 110, Hamilton, ON L8L 2X2, Canaa. aress for M. Bhanari: bhanam@mcmaster.ca Thomas A. 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